Total Synthesis of the Endocannabinoid Uptake Inhibitor Guineensine and SAR Studies.
endocannabinoid membrane transport
endocannabinoids
guineensine
natural products
total synthesis
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
04 09 2019
04 09 2019
Historique:
received:
29
06
2019
pubmed:
20
7
2019
medline:
25
8
2020
entrez:
20
7
2019
Statut:
ppublish
Résumé
Guineensine ((2E,4E,12E)-13-(benzo[d][1,3]dioxol-5-yl)-N-isobutyltrideca-2,4,12-trienamide) is a plant-derived natural product that inhibits reuptake of the endocannabinoid anandamide with sub-micromolar potency. We have established a highly efficient total synthesis of guineensine, which provided the natural product in only five steps from commercially available 3-nonyn-1-ol in 17 % overall yield, relying on the attachment of the benzodioxolyl moiety to the unsaturated fatty acid chain by means of a Suzuki coupling as the key step. Subsequent SAR studies revealed that replacement of the N-isobutyl group in the natural product by various alkyl, arylalkyl, or aryl groups is generally well tolerated, and derivatives could be identified that are slightly more potent anandamide reuptake inhibitors than guineensine itself. In contrast, modifications of the benzodioxolyl moiety led to decreased activity. Intriguingly, a change in the configuration of the C4=C5 double bond from E to Z was found to be very well tolerated, in spite of the associated change in the overall geometry of the molecule.
Identifiants
pubmed: 31322825
doi: 10.1002/cmdc.201900390
doi:
Substances chimiques
Alkenes
0
Arachidonic Acids
0
Endocannabinoids
0
Heterocyclic Compounds, 2-Ring
0
Polyunsaturated Alkamides
0
guineensine
0
anandamide
UR5G69TJKH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1590-1596Informations de copyright
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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